Previous studies have shown that the diaminoalkane side chain of chloroquine can be modified to produce a series of aminoquinoline analogs, many of which (40% of 75) are active against CQ-susceptible P. falciparum parasites, and some of which (20-23% of 75) are active against CQ-, mefloquine and multiply-resistant P. falciparum parasites. However, the rate-limiting step in the development of these compounds has been the slow pace of solution phase manual synthesis. In this proposal, we will develop solid phase organic synthetic strategies and solution phase (polymer supported) synthetic strategies based on modern combinatorial chemistry in order to circumvent this roadblock, and thus to permit the development of AQs and AQ combinations for clinical use in the treatment of human P. falciparum infection. The specific aims of this proposal are to: (l) Synthesize aminoquinoline analogs with potential antimalarial activity based on modern combinatorial chemistry to increase the diversity of the compounds available for testing and expand SAR studies, (2) test these compounds for antimalarial activity in vitro against chloroquine-susceptible and chloroquine-, mefloquine- and multiply-resistant Plasmodium falciparum, and (3) Screen promising aminoquinolines for their resistance to metabolic inactivation by the P-450 system in vitro. PROPOSED COMMERCIAL APPLICATIONS: Because of the worldwide importance and prevalence of infection with drug- resistant P. falciparum, the potential market is enormous, estimated at $100- 120M worldwide. In addition, the economic power of the market for antimalarials is increasing steadily. In Southeast Asia, India and China are malaria-endemic nations with drug resistant parasites that have substantial middle classes, as well as strong markets in South America, Brazil, and Colombia.